K2P18.1 translates T cell receptor signals into thymic regulatory T cell development

Tobias Ruck; Stefanie Bock; Steffen Pfeuffer; Christina B Schroeter; Derya Cengiz; Paul Marciniak; Maren Lindner; Alexander Herrmann; Marie Liebmann; Stjepana Kovac; Lukas Gola; Leoni Rolfes; Marc Pawlitzki; Nils Opel; Tim Hahn; Udo Dannlowski; Thomas Pap; Felix Luessi; Julian A Schreiber; Bernhard Wünsch; Tanja Kuhlmann; Guiscard Seebohm; Björn Tackenberg; Patricia Seja; Frank Döring; Erhard Wischmeyer; Achmet Imam Chasan; Johannes Roth; Luisa Klotz; Gerd Meyer Zu Hörste; Heinz Wiendl; Tobias Marschall; Stefan Floess; Jochen Huehn; Thomas Budde; Tobias Bopp; Stefan Bittner; Sven G Meuth

doi:10.1038/s41422-021-00580-z

K_2P18.1 translates T cell receptor signals into thymic regulatory T cell development

Cell Res. 2022 Jan;32(1):72-88. doi: 10.1038/s41422-021-00580-z. Epub 2021 Oct 26.

Authors

Tobias Ruck^#^{1

2}, Stefanie Bock^#³, Steffen Pfeuffer⁴, Christina B Schroeter⁴, Derya Cengiz^{4

3}, Paul Marciniak^{4

3}, Maren Lindner³, Alexander Herrmann⁴, Marie Liebmann³, Stjepana Kovac³, Lukas Gola³, Leoni Rolfes⁴, Marc Pawlitzki^{4

3}, Nils Opel⁵, Tim Hahn⁵, Udo Dannlowski⁵, Thomas Pap⁶, Felix Luessi⁷, Julian A Schreiber^{8

9}, Bernhard Wünsch⁸, Tanja Kuhlmann¹⁰, Guiscard Seebohm⁹, Björn Tackenberg¹¹, Patricia Seja¹², Frank Döring¹³, Erhard Wischmeyer¹³, Achmet Imam Chasan¹⁴, Johannes Roth¹⁴, Luisa Klotz³, Gerd Meyer Zu Hörste³, Heinz Wiendl³, Tobias Marschall¹⁵, Stefan Floess¹⁶, Jochen Huehn¹⁶, Thomas Budde¹⁷, Tobias Bopp¹⁸, Stefan Bittner⁷, Sven G Meuth^{4

3}

Affiliations

¹ Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany. [email protected].
² Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany. [email protected].
³ Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.
⁴ Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
⁵ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
⁶ Institute of Experimental Musculoskeletal Medicine (IMM), University of Münster, Münster, Germany.
⁷ Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
⁸ Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Münster, Germany.
⁹ Cellular Electrophysiology and Molecular Biology, Institute for Genetics of Heart Diseases (IfGH), University of Münster, Münster, Germany.
¹⁰ Institute of Neuropathology, University of Münster, Münster, Germany.
¹¹ Department of Neurology, Philipps-University, Marburg, Germany.
¹² Laboratory of Neurobiology, University of Helsinki, Helsinki, Finland.
¹³ Molecular Electrophysiology, Institute of Physiology and Center of Mental Health, University of Würzburg, Würzburg, Germany.
¹⁴ Institute of Immunology, University of Münster, Münster, Germany.
¹⁵ Institute for Medical Biometry and Bioinformatics, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
¹⁶ Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
¹⁷ Institute for Physiology I, University of Münster, Münster, Germany.
¹⁸ Institute of Immunology, Focus Program Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

^# Contributed equally.

Abstract

It remains largely unclear how thymocytes translate relative differences in T cell receptor (TCR) signal strength into distinct developmental programs that drive the cell fate decisions towards conventional (Tconv) or regulatory T cells (Treg). Following TCR activation, intracellular calcium (Ca²⁺) is the most important second messenger, for which the potassium channel K_2P18.1 is a relevant regulator. Here, we identify K_2P18.1 as a central translator of the TCR signal into the thymus-derived Treg (tTreg) selection process. TCR signal was coupled to NF-κB-mediated K_2P18.1 upregulation in tTreg progenitors. K_2P18.1 provided the driving force for sustained Ca²⁺ influx that facilitated NF-κB- and NFAT-dependent expression of FoxP3, the master transcription factor for Treg development and function. Loss of K_2P18.1 ion-current function induced a mild lymphoproliferative phenotype in mice, with reduced Treg numbers that led to aggravated experimental autoimmune encephalomyelitis, while a gain-of-function mutation in K_2P18.1 resulted in increased Treg numbers in mice. Our findings in human thymus, recent thymic emigrants and multiple sclerosis patients with a dominant-negative missense K_2P18.1 variant that is associated with poor clinical outcomes indicate that K_2P18.1 also plays a role in human Treg development. Pharmacological modulation of K_2P18.1 specifically modulated Treg numbers in vitro and in vivo. Finally, we identified nitroxoline as a K_2P18.1 activator that led to rapid and reversible Treg increase in patients with urinary tract infections. Conclusively, our findings reveal how K_2P18.1 translates TCR signals into thymic T cell fate decisions and Treg development, and provide a basis for the therapeutic utilization of Treg in several human disorders.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Forkhead Transcription Factors
Humans
Mice
NF-kappa B
Potassium Channels*
Receptors, Antigen, T-Cell*
T-Lymphocytes, Regulatory*
Thymocytes
Thymus Gland

Substances

Forkhead Transcription Factors
NF-kappa B
Potassium Channels
Receptors, Antigen, T-Cell

Abstract

Publication types

MeSH terms

Substances

Grants and funding